Hypertension is a major public health problem worldwide affecting over 50 million Americans. It is a major risk factor for target organ damage resulting in coronary artery disease, heart failure, stroke, and kidney disease. Large epidemiological surveys have shown that more elderly women than men have hypertension. Whether this specific effect of sex is grounded in equally specific pathophysiology which could "personalize" the selection of antihypertensive therapy and improve the response to treatment is unknown. The primary goal of this research proposal is to determine the mechanisms underlying sex differences in hypertension in sedentary seniors (i.e., =65 years old), and to determine whether exercise training in combination with antihypertensive drug treatment is effective in elderly women. Using the innovative techniques of microneurography, Doppler ultrasound, and tonometry, Specific Aim 1 will test the hypothesis that sympathetic neural activity is augmented in elderly hypertensive women. Autonomic function tests will be performed;sympathetic neural responses, vasoconstrictor capability, transduction of sympathetic traffic into vascular resistance, and baroreflex function will be compared in elderly normotensive and hypertensive men and women;Specific Aim 2 will test the hypothesis that ventricular-arterial stiffening is more prominent in elderly hypertensive women than men. Pulse wave velocity, dynamic systolic arterial elastance, aortic artery augmentation pressure and index, total arterial compliance, cardiac size, and aortic pulsative dimensions will be compared between normotensive and hypertensive men and women;Specific Aim 3 will test the hypothesis that a long-term exercise training program in combination with antihypertensive drug treatment is more effective than pharmacologic therapy alone in hypertensive seniors, and the responses to exercise training differ between sexes. Patients enrolled in Specific Aim 1 and 2 studies will be assigned randomly either to drug treatment alone [a combination of losartan (AT1 receptor antagonist) and hydrochlorothiazide (diuretic), Hyzaar plus contact control] or to exercise training (Hyzaar and exercise training) for 6 months, the same protocols employed in Specific Aim 1 and 2 will be repeated after treatment, and results will be compared among groups and between sexes. Upon completion of this project, we will have obtained novel and clinically important information regarding the nature of hypertension associated with aging and sex, the selection of antihypertensive therapy, and the responses to treatment in elderly hypertensive men and women. We will identify the mechanisms underlying sex differences in hypertension and antihypertensive therapy in seniors, which may lead to more effective therapies for this particularly patient population. PUBLIC HEALTH RELEVANCE High blood pressure is a major public health problem worldwide affecting over 50 million Americans and resulting in heart disease, stroke, and kidney disease. It has been found that more elderly women than men have high blood pressure, but the mechanisms are completely unknown and whether the treatment should differ in older male and female patients is unclear. The primary goal of this project is to address these important issues. Results obtained will provide novel insights into the mechanisms for sex differences in high blood pressure in the elderly, the selection of treatment, and the responses to treatment in this patient population.